Patients with KRAS-G12C Mutation
Thirteen percent (13%) of patients with non–small-cell lung cancers (NSCLC) and 1-3% patients with colorectal (CRC) and other cancers carry KRAS p.G12C driver mutations. The only therapy targeted for this particular mutation, approved by the USFDA for this group of patients, is Sotorasib. It is available under the brand name Lumakras.
Sotorasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test. It is meant for patients who have received at least one prior systemic therapy. Patients with NSCLC and CRC should be selected for therapy based only on the presence of KRAS G12C mutation in tumor or plasma samples.
The USFDA approved Sotorasib on the 28 th May, 2021. The approval was based on CodeBreaK 100 study conducted on 124 NSCLC patients harbouring KRAS G12C mutation. The objective response observed in these 124 patients treated with Sotorasib was 37% (95% CI). Interestingly, 3% of patients had a complete response, while 34% had partial response.
It must be noted that, although all the 124 patients enrolled in the study carried the KRAS G12C driver mutation, only 37% of them responded to Sotorasib therapy, with only 3% of them having complete response. The rest of the patients did not benefit from the targeted therapy, although they qualified for the treatment.
This clearly suggests that the presence of the driver mutation alone is not sufficient for therapeutic success. Cancer develops through a multi-step mutagenesis process, involving genetic changes in a variety of oncogenes and tumor suppressor genes. Whether a patient having a KRAS G12C mutation will respond to Sotorasib or not depends on multiple other factors like co-occurring mutations in genes related to the biological pathway impacted by KRAS signalling, upstream and downstream signalling mediators of KRAS protein, and cross-talks, resistance or negative feedback signalling loops.
OncoDynamiX looks at a patient’s cancer biology holistically, including all the factors mentioned above. OncoDynamiX can help in selection of appropriate anti-cancer drug or combination of drugs that will help to increase the clinical efficacy of Sotorasib in patients with KRAS G12C mutation who did not respond to Sotorasib.
Author:Ramesh Jayaraman-Chief Scientific Officer, OncoDynamiX Lifesciences.
References:
- New Drug Application (NDA): 214665; Company: AMGEN INC https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=214665
- Nakajima EC, Drezner N, Li X, Mishra-Kalyani PS, Liu Y, Zhao H, Bi Y, Liu J, Rahman A, Wearne E, Ojofeitimi I, Hotaki LT, Spillman D, Pazdur R, Beaver JA, Singh H. FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC. Clin Cancer Res. 2022; 28(8):1482-1486.
- Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021 Jun 24;384(25):2371-2381. doi: 10.1056/NEJMoa2103695. Epub 2021 Jun 4. PMID: 34096690; PMCID: PMC9116274.